cGMP (guanosine-3′,5′-cyclic monophosphate, cyclic guanosine monophosphate) is a cyclic nucleotide found in animal and plant cells. It is an intracellular second messenger and is involved in various cell responses. It can be hydrolyzed by PDE-5 (phosphodiesterase-5). When PDE-5 is inhibited, the cGMP will increase, which will result in various physiological effects, e.g., relaxation of the vascular smooth muscle. Therefore, PDE-5 inhibitors can be used for the treatment of diseases, including hypertension, heart failure, pulmonary hypertension, erectile dysfunction, prostatic hyperplasia and female sexual dysfunction, etc.
Erectile dysfunction (ED) is the most common sexual dysfunction of men, characterized by continuous inability to achieve or maintain a penile erection for satisfactory sexual performance. ED is classified into organic ED, psychological ED and mixed ED. Although ED is non-fatal, it has a significant negative impact on the life quality as well as relationship of the couples.
There have been many treatments for ED, mainly including three types: peripheral drug treatment, central drug treatment and gene therapy. Peripheral drug treatment mainly employs phosphodiesterase-5 inhibitors (e.g. Sildenafil), also includes the employment of narceine, soluble Guanylate cyclase activator, Rho kinase agonist or local alprostadil. Central drug treatment employs dopamine receptor agonist, α-adrenergic receptor antagonist, 5-hydroxy tryptamine (5-HT) receptor agonist, oxytocin, oxytocin receptor agonist, etc. Gene therapy is based on the fact that ion channel is the essential substance for regulating the tension of smooth muscle of corpus cavernosum, and relaxes corpus cavernosum by injecting into corpus cavernosum the plasmid hMaxi-K (pVAX-hSLO) expressing hSlo gene, which expresses in the smooth muscle of corpus cavernosum and generates more potassium ion channels.
Currently, there are many treatments for ED. Phosphodiesterase-5 (PDE-5) inhibitors represented by Sildenafil (Viagra) are the first-line drugs for treating ED, also the most favourite treatment of the patients. At present, PDE-5 inhibitors on the market include Sildenafil, Vardenafil, Tadalafil, Udenafil and Avanafil. These drugs are taken orally and conveniently, and have fast and definite effect. Among them, Sildenafil and Tadalafil are important profitable products of Pfizer and Eli Lilly, respectively. Thus, these drugs have a huge potential market.

The structures of the compounds as disclosed in the patent application WO200119802 (Publication date: 2001 Mar. 22) of Tanabe Seiyaku Co., LTD are as following:

From the view of epidemiology, many elderly male patients who suffer from ED may also suffer from other diseases of genitourinary system, e.g. lower urinary tract symptoms (LUTS) such as benign prostatic hyperplasia (BPH), overactive bladder (OAB) and the like. These diseases bring about great distress to the elderly patients, and seriously affect their life. By pathological analysis, it has been found that the pathogenesis of ED and LUTS are the same, which are both in relevance to contraction of smooth muscle or proliferation of smooth muscle cell. Therefore, it is possible that LUTS, which has the same pathogenesis, can be treated by using PDE-5 inhibitor. Tadalafil has been approved by FDA for use in the treatment of benign prostatic hyperplasia.
With the clinical application of PDE-5 inhibitors, some potential safety problems of the drugs are emerging. Among the drugs, Sildenafil and Vardenafil not only have inhibition on PDE-5, but also have a certain inhibitory effect on PDE-6, which affects the function of retina. As a result, the two drugs affect the eyesight of the users. In this aspect, reports about Sildenafil are more than Vardenafil. Therefore, the two drugs have a poor selectivity for PDE-5. Tadalafil has a good selectivity for PDE-6, however, it has a certain inhibitory effect on PDE-11. Although the clinical pharmacological effects of PDE-11 are unknown, there is still potential risk. It was reported in some references that Tadalafil could cause an osphyalgia. Whether the symptom of osphyalgia is related to PDE-11 remains to be proven. In addition, the increased dosage of Vardenafil due to its low bioavailability is a disadvantage for long-term use of patient. The half-life of Tadalafil, as long as about 16 h in human, can easily result in drug interactions if a patient takes other drugs simultaneously. For example, the combined use of nitrate drugs and Tadalafil can excessively decrease the blood pressure, which can be life-threatening.
Avanafil, one of the second-generation PDE-5 inhibitors, has a good selectivity to PDE-6 , with the ration PDE-6/5 of about 120. Moreover, it has no inhibitory effect on PDE-11, which guarantees the safety of clinical medication. However, its enzymatic activity in vitro is low, and the clinical dosage is high (50 mg, 100 mg and 200 mg), higher than Sildenafil, Vardenafil and Tadalafil. This can be a hazard for the safety of clinical medication. In addition, the increase of dosage will result in an increase of treatment costs. There is large potential improvement for Avanafil from the view of pharmacoeconomics. The most common adverse reactions reported in the clinical studies included headache, flushing, nasal congestion, nasopharyngitis and backache. A rare side effect of Avanafil is sudden decrease or loss of eyesight of the men taking this drug. Due to its low bioavailability, high clinical dosage and short half-life (about 1.2 h in human), Avanafil can only be used in single therapy of ED, but is not suitable for treating BPH, OAB and other diseases. Consequently, it is significant to develop a PDE-5 inhibitor with a high selectivity for PDE-5, a stronger pharmacological activity, a high bioavailability, more safety as well as an appropriate half-life (long but not overlong) so as to improve the life quality of elderly patients (treating ED, BPH and LUTS).